Advertisement

Extrahepatic Manifestations of Hepatitis C Virus Infection

  • Çetin Karaca
Chapter

Abstract

The hepatitis C virus (HCV) is a hepatotropic virus that causes liver cirrhosis and hepatocellular cancer, but it is now considered a systemic disease because of the additional HCV-associated extrahepatic manifestations (EHMs) that occur. HCV infection is a global health problem, with 150–170 million people being chronically infected. It is estimated that about 350,000 patients die from HCV-related complications. However, the risks of mortality and morbidity are underestimated because studies do not take into account extrahepatic outcomes of chronically infected HCV patients. Extrahepatic complications of HCV infection have been shown to be more prevalent in large cohort studies, where two thirds of patients chronically infected with HCV infection have experienced EHMs (Cacoub et al., Arthritis Rheum 42:2204–2212, 1999; El-Serag et al., Hepatology 36:1439–1445, 2002). Some of these EHMs are well documented and more common, while others are rare or their association with HCV is unproven. HCV-associated autoimmune or lymphoproliferative disorders, from benign mixed cryoglobulinemia to frank lymphomas, have been reported. More recently, many other extrahepatic HCV-related disorders have been reported, including cardiovascular, renal, metabolic, and central nervous system diseases. Viral eradication of HCV has significantly reduced the rates of hepatic and extrahepatic deaths (Cacoub et al., Arthritis Rheum 42:2204–2212, 1999; Adinolfi et al., World J Gastroenterol 20:3410–3417, 2014; Zignego et al., Dig Liver Dis 39:2–17, 2007; Lee et al., J Infect Dis 206:469–477, 2012; Omland et al., Clin Gastroenterol Hepatol 9:71–78, 2011; Uto et al., Hepatology 50:393–399, 2009; Hsu et al., Hepatology 59:1293–1302, 2014). The aim of this chapter is to give a brief objective approach to the epidemiology, pathogenesis, and treatment of HCV-associated EHMs.

Keywords

Chronic HCV infection Extrahepatic manifestations 

Abbreviations

Anti-CCP

Anti–cyclic citrullinated peptide

DM

Diabetes mellitus

EHM

Extrahepatic manifestation

EMC

Essential mixed cryoglobulinemia

HCV

Hepatitis C virus

HFE

Homeostatic iron regulator

HLA

Human leukocyte antigen

HRQoL

Health-related quality of life

IR

Insulin resistance

KDIGO

Kidney Disease Improving Global Outcomes

LP

Lichen planus

NHL

Non-Hodgkin lymphoma

PCT

Porphyria cutanea tarda

RF

Rheumatoid factor

SVR

Sustained virological response

UROD

Uroporphyrinogen decarboxylase

References

  1. 1.
    Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment virus C. Arthritis Rheum. 1999;42(10):2204–12.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    El-Serag HB, et al. Extrahepatic manifestations of hepatitis C among United States male veterans. Hepatology. 2002;36(6):1439–45.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Adinolfi LE, et al. Chronic hepatitis C virus infection and atherosclerosis: clinical impact and mechanisms. World J Gastroenterol. 2014;20(13):3410–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Zignego AL, et al. Extrahepatic manifestations of hepatitis C virus infection: a general overview and guidelines for a clinical approach. Dig Liver Dis. 2007;39(1):2–17.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Lee MH, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206(4):469–77.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Omland LH, et al. Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol. 2011;9(1):71–8.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Uto H, et al. Increased rate of death related to presence of viremia among hepatitis C virus antibody–positive subjects in a community-based cohort study. Hepatology. 2009;50(2):393–9.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hsu YC, et al. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology. 2014;59(4):1293–302.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016;3(1):3–14.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lunel F, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106(5):1291–300.PubMedCrossRefGoogle Scholar
  11. 11.
    Terrier B, Cacoub P. Renal involvement in HCV-related vasculitis. Clin Res Hepatol Gastroenterol. 2013;37(4):334–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Cacoub P, et al. Extrahepatic manifestations of chronic hepatitis C virus infection. Dig Liver Dis. 2014;46(Suppl 5):S165–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Ferri C, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33(6):355–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Cacoub P, et al. Rheumatologic manifestations of hepatitis C virus infection. Clin Liver Dis. 2017;21(3):455–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Sene D, et al. Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol. 2004;31(11):2199–206.PubMedGoogle Scholar
  16. 16.
    Pietrogrande M, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus–infected patients. Autoimmun Rev. 2011;10(8):444–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Saadoun D, et al. Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. 2006;54(11):3696–706.PubMedCrossRefGoogle Scholar
  18. 18.
    Sise ME, et al. Treatment of hepatitis C virus–associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016;63(2):408–17.PubMedCrossRefGoogle Scholar
  19. 19.
    Emery JS, et al. Efficacy and safety of direct acting antivirals for the treatment of mixed cryoglobulinemia. Am J Gastroenterol. 2017;112(8):1298–308.PubMedCrossRefGoogle Scholar
  20. 20.
    Giordano TP, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297(18):2010–7.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Duberg AS, et al. Non-Hodgkin’s lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology. 2005;41(3):652–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Tursi A, et al. Detection of HCV RNA in gastric mucosa–associated lymphoid tissue by in situ hybridization: evidence of a new extrahepatic localization of HCV with increased risk of gastric malt lymphoma. Am J Gastroenterol. 2002;97(7):1802–6.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gisbert JP, et al. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology. 2003;125(6):1723–32.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Hermine O, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89–94.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Silvestri F, et al. Hepatitis C virus infection among cryoglobulinemic and non-cryoglobulinemic B-cell non-Hodgkin’s lymphomas. Haematologica. 1997;82(3):314–7.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kawamura Y, et al. Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med. 2007;120(12):1034–41.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Maciocia N, O’Brien A, Ardeshna K. Remission of follicular lymphoma after treatment for hepatitis C virus infection. N Engl J Med. 2016;375(17):1699–701.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Ennishi D, et al. Hepatic toxicity and prognosis in hepatitis C virus–infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood. 2010;116(24):5119–25.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Deybach JC, et al. European Porphyria Initiative (EPI): a platform to develop a common approach to the management of porphyrias and to promote research in the field. Physiol Res. 2006;55(Suppl 2):S67–73.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Alla V, Bonkovsky HL. Iron in nonhemochromatotic liver disorders. Semin Liver Dis. 2005;25(4):461–72.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Elder GH. Update on enzyme and molecular defects in porphyria. Photodermatol Photoimmunol Photomed. 1998;14(2):66–9.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Liu LU, Phillips J, Bonkovsky H. Familial porphyria cutanea tarda. In: Adam MP, et al., editors. GeneReviews®. Seattle: University of Washington; 1993.Google Scholar
  33. 33.
    Frank J, Poblete-Gutierrez P. Porphyria cutanea tarda—when skin meets liver. Best Pract Res Clin Gastroenterol. 2010;24(5):735–45.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Besur S, et al. Clinically important features of porphyrin and heme metabolism and the porphyrias. Meta. 2014;4(4):977–1006.Google Scholar
  35. 35.
    Bonkovsky HL, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. 1998;27(6):1661–9.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Garcovich S, et al. Cutaneous manifestations of hepatitis C in the era of new antiviral agents. World J Hepatol. 2015;7(27):2740–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Nishina S, et al. Hepatitis C virus–induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134(1):226–38.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Gisbert JP, et al. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol. 2003;39(4):620–7.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol. 2001;26(3):225–32.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Puy H, Gouya L, Deybach JC. Porphyrias. Lancet. 2010;375(9718):924–37.PubMedCrossRefGoogle Scholar
  41. 41.
    Schulenburg-Brand D, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369–84, ix.PubMedCrossRefGoogle Scholar
  42. 42.
    Linet MS, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol. 1999;149(11):1010–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Sayiner M, et al. Dermatologic manifestations of chronic hepatitis C infection. Clin Liver Dis. 2017;21(3):555–64.PubMedCrossRefGoogle Scholar
  44. 44.
    Szlendak U, Bykowska K, Lipniacka A. Clinical, biochemical and molecular characteristics of the main types of porphyria. Adv Clin Exp Med. 2016;25(2):361–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematol Am Soc Hematol Educ Program. 2012;2012:19–27.Google Scholar
  46. 46.
    Fernandez I, et al. Porphyria cutanea tarda as a predictor of poor response to interferon alfa therapy in chronic hepatitis C. Scand J Gastroenterol. 2003;38(3):314–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Azim J, McCurdy H, Moseley RH. Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C. World J Gastroenterol. 2008;14(38):5913–5.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Desai TK, et al. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci. 2008;53(3):815–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Aguilera P, Laguno M, To-Figueras J. Treatment of chronic hepatitis with boceprevir leads to remission of porphyria cutanea tarda. Br J Dermatol. 2014;171(6):1595–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Le Cleach L, Chosidow O. Clinical practice: lichen planus. N Engl J Med. 2012;366(8):723–32.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med. 1995;123(8):615–20.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Shengyuan L, et al. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145(9):1040–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Nagao Y, et al. Genome-wide association study identifies risk variants for lichen planus in patients with hepatitis C virus infection. Clin Gastroenterol Hepatol. 2017;15(6):937–44. e5PubMedCrossRefGoogle Scholar
  54. 54.
    Abdallah MA, et al. Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53(2):247–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Khanna VJ, et al. Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc. Arch Dermatol. 2000;136(6):755–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Hivnor CM, et al. Necrolytic acral erythema: response to combination therapy with interferon and ribavirin. J Am Acad Dermatol. 2004;50(5 Suppl):S121–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Tsai TF, et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J Dermatol Sci. 2011;63(1):40–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Imafuku S, Naito R, Nakayama J. Possible association of hepatitis C virus infection with late-onset psoriasis: a hospital-based observational study. J Dermatol. 2013;40(10):813–8.PubMedGoogle Scholar
  59. 59.
    Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165(5):1037–43.PubMedCrossRefGoogle Scholar
  60. 60.
    Cohen AD, et al. Psoriasis associated with hepatitis C but not with hepatitis B. Dermatology. 2010;220(3):218–22.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Snast I, et al. Risk for hepatitis B and C virus reactivation in patients with psoriasis on biologic therapies: a retrospective cohort study and systematic review of the literature. J Am Acad Dermatol. 2017;77(1):88–97.e5.CrossRefPubMedGoogle Scholar
  62. 62.
    Cacoub P, et al. Extrahepatic manifestations associated with hepatitis C virus infection: a prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine (Baltimore). 2000;79(1):47–56.CrossRefGoogle Scholar
  63. 63.
    Himoto T, Masaki T. Extrahepatic manifestations and autoantibodies in patients with hepatitis C virus infection. Clin Dev Immunol. 2012;2012:871401.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Hsieh MY, et al. Antinuclear antibody is associated with a more advanced fibrosis and lower RNA levels of hepatitis C virus in patients with chronic hepatitis C. J Clin Pathol. 2008;61(3):333–7.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Younossi Z, et al. Extrahepatic manifestations of hepatitis C: a meta-analysis of prevalence, quality of life, and economic burden. Gastroenterology. 2016;150(7):1599–608.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Antonelli A, et al. Thyroid disorders in chronic hepatitis C. Am J Med. 2004;117(1):10–3.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid. 2003;13(6):547–51.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Mohammed RH, et al. Prevalence of rheumatologic manifestations of chronic hepatitis C virus infection among Egyptians. Clin Rheumatol. 2010;29(12):1373–80.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831–44.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Petit JM, et al. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35(2):279–83.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Bigam DL, et al. Hepatitis C–related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology. 2000;32(1):87–90.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Moucari R, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134(2):416–23.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Milner KL, et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology. 2010;138(3):932–41.e1–3.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Romero-Gomez M, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721–7.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Arase Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739–44.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Conjeevaram HS, et al. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology. 2011;140(2):469–77.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Johnson RJ, et al. Hepatitis C virus–associated glomerulonephritis: effect of alpha-interferon therapy. Kidney Int. 1994;46(6):1700–4.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    McGuire BM, et al. Brief communication: glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation. Ann Intern Med. 2006;144(10):735–41.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2008;109:S1–99.Google Scholar
  80. 80.
    Morsica G, et al. Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients. J Med Virol. 1997;53(3):252–4.PubMedCrossRefGoogle Scholar
  81. 81.
    Cozzi A, et al. Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients. J Viral Hepat. 2006;13(6):402–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Byrnes V, et al. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol. 2012;56(3):549–56.PubMedCrossRefGoogle Scholar
  83. 83.
    Thein HH, et al. Improved cognitive function as a consequence of hepatitis C virus treatment. HIV Med. 2007;8(8):520–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Kallman J, et al. Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci. 2007;52(10):2531–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Heeren M, et al. Active at night, sleepy all day—sleep disturbances in patients with hepatitis C virus infection. J Hepatol. 2014;60(4):732–40.PubMedCrossRefGoogle Scholar
  86. 86.
    Bonkovsky HL, et al. Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. J Hepatol. 2007;46(3):420–31.PubMedCrossRefGoogle Scholar
  87. 87.
    Marcellin P, et al. Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study. Liver Int. 2011;31(4):516–24.PubMedCrossRefGoogle Scholar
  88. 88.
    Younossi ZM, et al. Minimal impact of sofosbuvir and ribavirin on health related quality of life in chronic hepatitis C (CH-C). J Hepatol. 2014;60(4):741–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Fukui M, et al. Hepatitis C virus and atherosclerosis in patients with type 2 diabetes. JAMA. 2003;289(10):1245–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Domont F, Cacoub P. Chronic hepatitis C virus infection, a new cardiovascular risk factor? Liver Int. 2016;36(5):621–7.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Gill K, et al. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int. 2016;10(3):415–23.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Hsu YC, et al. Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection. Gut. 2015;64(3):495–503.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Wong RJ, et al. Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature. Dig Dis Sci. 2014;59(7):1586–93.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Çetin Karaca
    • 1
  1. 1.Gastroenterology DepartmentIstanbul School of Medicine, Istanbul UniversityIstanbulTurkey

Personalised recommendations